CONTACT

KRIMM Isabelle
Chef d’Équipe
Chargé de Recherche CNRS
04 78 77 75 86
isabelle.krimm@univ-lyon1.fr

LE BORGNE Marc
Professeur des Universités
04 78 77 75 86
marc.le-borgne@univ-lyon1.fr

DELCROS Jean-Guy
Chargé de Recherche HC INSERM
04 78 77 75 85
jeanguy.delcros@lyon.unicancer.fr

MULARONI Angélique
Maître de Conférences des Universités
04 78 77 75 85
angelique.mularoni@univ-lyon1.fr

MARMINON DAVOUST Christelle
Maître de Conférences des Universités
04 78 77 28 67
christelle.marminon-davoust@univ-lyon1.fr

ROLLAND DE RAVEL Marc
Ingénieur d’Étude INSERM
04 78 77 28 67
marc.rolland-de-ravel@univ-lyon1.fr

BRION Béatrice
Technicienne HC CNRS
04 78 77 75 86
beatrice.brion@ens-lyon.fr

PRETO Jordane
Postdoctorant
jordane.preto@univ-lyon1.fr

BANCET Alexandre
Doctorant
alexandre.bancet@etu.univ-lyon1.fr

GORNY Hubert
Doctorant
hubert.gorny@etu.univ-lyon1.fr

Voir les objectifs et projets Voir les publications

OBJECTIVES

Our team develops small bioactive molecules with two objectives:
-    the design of small-molecule tools to explore biological pathways involved in cancer (chemical probes)
-    the design of therapeutic compounds to fight cancer (drug-candidate).

Our multidisciplinary team designs and synthesizes novel chemical structures using in-silico approaches, biophysical technics and structural biology. These molecules are evaluated to optimize their activity and study their biological impact.  


Strategy for the design of small molecules targeting biological targets 
(fragment-based approaches and structure-based methods)

PROJECTS

1.       Design of small-molecule tools for fundamental research:  development of molecules that modulate the activity of the ionic channel VDAC1

VDAC1, located in the outer membrane of mitochondria is a ionic channel whose function is crucial for cell survival and metabolic pathways. VDAC1 is also involved in apoptosis, notably through its interaction with members of the BCl-2 family. By interfering with the flux of Ca2+, VDAC1 may also play a role in the invasion of cancer cells and the formation of metastases.
To have a better understanding of the role of VDAC in cancer cells, and possibly to validate VDAC1 as a therapeutic target, we are developing specific ligands of VDAC1 capable to modulate the channel activity.

2.       Design of molecules modulating the CK2 kinase activity for therapeutic purposes

An increased expression in different cancer lines, an ability to act as a suppressor of apoptosis an promote cell survival, associated with a strong implication to reinforce a drug resistance phenotype are all characteristics which underline the interest in the protein kinase CK2 as a therapeutic target. Most of the inhibitors identified are ATP-mimetic molecules, one of which, CX-4945 (silmitasertib), has made its way into phase II clinical trial. With this mode of action, these inhibitors exhibit high toxicity, in particular due to a lack of specificity for their target, which compromises their clinical success. In order to offer therapeutic alternatives, the team is developing molecules that disrupt the activity of this protein kinase by targeting sites other than its ATP catalytic site.

Other projects include :
-    the design of ABCG2 inhibitors (Collaboration P. Falson, Lyon).
-    the development of NMR-based approaches for fragment-screening against GPCR (Collaboration R. Wagner, Strasbourg).

PUBLICATIONS

Prandina A, Herfindal L, Radix S, Rongved P, Døskeland S, Le Borgne M, Perret F: Enhancement of iodinin solubility by encapsulation into cyclodextrin nanoparticles. J Enzyme Inhib Med Chem 33: 370–375, 2018.

Radix S, Jordheim AD, Rocheblave L, N'Digo S, Prignon AL, Commun C, Michalet S, Dijoux-Franca MG, Mularoni A, Walchshofer N: N,N'-disubstituted cinnamamide derivatives potentiate ciprofloxacin activity against overexpressing NorA efflux pump Staphylococcus aureus 1199B strains. Eur J Med Chem 150:900907, 2018.

Sylwia Bloch S, Bożena Nejman-Faleńczyk B, Karolina Pierzynowska K, Ewa Piotrowska E, Alicja Węgrzyn A, Marminon C, Bouaziz Z, Nebois P, Jose J, Le Borgne M, Saso L, Węgrzyn G: Inhibition of Shiga toxin-converting bacteriophage development by novel antioxidant compounds. J Enzyme Inhib Med Chem 33: 639–650, 2018.

Bouzina A, Bechlem K, Berredjem H, Belhani B, Becheker I, Lebreton J, Le Borgne M, Bouaziz Z, Marminon C, Berredjem M: Synthesis, spectroscopic characterization, and in vitro antibacterial evaluation of novel functionalized sulfamidocarbonyloxyphosphonates. Molecules 23: E1682, 2018.

Bouchouit M, Bouacida S, Zouchoune B, Merazig H, Bua S, Bouaziz Z, Le Borgne M, Supuran CT, Bouraiou A: Synthesis, X-ray structure, in silico calculation, and carbonic anhydrase inhibitory properties of benzylimidazole metal complexes. J Enzyme Inhib Med Chem 33: 1150–1159, 2018.

Schnaars C, Kildahl-Andersen G, Prandina A, Popal R, Large Radix S, Le Borgne M, Gjøen T, Andresen AMS, Heikal A, Økstad OA, Fröhlich C, Samuelsen Ø, Lauksund S, Jordheim LP, Rongved P, Åstrand OAH: Synthesis and preclinical evaluation of TPA-based zinc chelators as metallo-β-lactamase inhibitors. ACS Infect Dis 4: 1407–1422, 2018.

Braun F, Bertoletti N, Möller G, Adamski J, Frotscher M, Guragossian N, Patrícia Gírio PA, Le Borgne M, Ettouati L, Falson P, Müller S, Vollmer G, Heine A, Klebe G, Marchais-Oberwinkler S: Structure-based design and profiling of novel 17β-HSD14 inhibitors. Eur J Med Chem 155: 61–76, 2018.

Igonet S, Raingeval C, Cecon E, Pučić-Baković M, Lauc G, Cala O, Baranowski M, Perez J, Jockers R, Krimm I, Jawhari A. Sci Rep 8: 81428149, 2018.

Nacereddine A, Bollacke A, Roka E, Marminon C, Bouaziz Z, Fenyvesi F, Bácskay I, Jose J, Perret F, Le Borgne M: Self-assembled supramolecular nanoparticles improve the cytotoxic efficacy of CK2 inhibitor THN7. Pharmaceuticals 11: E10, 2018.

Wischhusen J, Wilson KE, Delcros JG, Molina-Peña R, Gibert B, Jiang S, Ngo J, Goldschneider D, Mehlen P, Willmann JK, Padilla F: Ultrasound molecular imaging as a non-invasive companion diagnostic for netrin-1 interference therapy in breast cancer. Theranostics 8: 51265142, 2018.

Prandina A, Radix S, Le Borgne M, Jordheim LP, Bousfiha Z, Fröhlich C, Samuelsen Ø, Frøvold E, Rongved P, Åstrand OAH: Synthesis and biological evaluation of new dipicolylamine zinc chelators as metallo-β-lactamase inhibitors. Tetrahedron 75: 1525–1540, 2019.

Ettouati L, Senta-Loys Z, Bourgeois S, Fenet B, Le Borgne M, Fessi H: Behaviour of tetrabenazine in acid medium: Reassessment and impact on formulation. Pharmaceutics 11: E44, 2019.

Charaabi S, Tchara L, Marminon C, Bouaziz Z, Holtzinger G, Pensé-Lhéritier AM, Le Borgne M, Issa S: A comparative adsorption study of benzophenone-3 onto synthesized lipophilic organosilicate, Laponite and montmorillonite. Appl Clay Sci 170: 114–124, 2019.

Alameh G, Emptoz-Bonneton A, Rolland de Ravel M, Matera EL, Mappus E, Balaguer P, Rocheblave L, Lomberget T, Dumontet C, Le Borgne M, Pugeat M, Grenot C, Cuilleron CY: In vitro modulation of multidrug resistance by pregnane steroids and in vivo inhibition of tumour development by 7α-OBz-11α(R)-OTHP-5β-pregnanedione in K562/R7 and H295R cell xenografts. J Enzyme Inhib Med Chem 34: 684–691, 2019.

Kildahl-Andersen G, Schnaars C, Prandina A, Radix S, Le Borgne M, Jordheim LP, Gjøen T, Andresen AMS, Lauksund S, Fröhlich C, Samuelsen Ø, Rongved P, Åstrand OAH: Synthesis and biological evaluation of zinc chelating compounds as metallo-β-lactamase inhibitors. MedChemComm 10: 528537, 2019.

Raingeval C, Cala O, Brion B, Le Borgne M, Hubbard RE, Krimm I: 1D NMR WaterLOGSY as an efficient method for fragment-based lead discovery. J Enzyme Inhib Med Chem 34: 12181225, 2019.

Bayart C, Jean E, Paillagot M, Renoud A, Raillard A, Paladino J, Le Borgne M: Comparison of SEC and AF4 analytical tools for size estimation of typhoid Vi polysaccharides. Anal Methods 11: 4851-4858, 2019.

Kufareva I, Bestgen B, Brear P, Prudent R, Laudet B, Moucadel V, Ettaoussi M, Sautel CF, Krimm I, Engel M, Filhol O, Borgne ML, Lomberget T, Cochet C, Abagyan R: Discovery of holoenzyme-disrupting chemicals as substrate-selective CK2 inhibitors. Sci Rep 9: 15893, 2019.

Preto J, Gentile F: Assessing and improving the performance of consensus docking strategies using the DockBox package. J Comput Aided Mol Des 33: 817–829, 2019.

Klejborowska G, Urbaniak A, Preto J, Maj E, Moshari M, Wietrzyk J, Tuszynski JA, Chambers C, Huczyński A: Synthesis, biological evaluation and molecular docking studies of new amides of 4-bromothiocolchicine as anticancer agents. Bioorg Med Chem 27: 115144, 2019.

Park S, Guo Y, Negre J, Preto J, Smithers CC, Azad AK, Overduin M, Murray AG, Eitzen G: Fgd5 is a Rac1-specific Rho GEF that is selectively inhibited by aurintricarboxylic acid. Small GTPases 1-14, 2019. doi: 10.1080/21541248.2019.1674765.

Kalra AP, Kar P, Preto J, Rezania V, Dogariu A, Lewis JD, Tuszynski JA, Shankar K: Behavior of α-β tubulin in DMSO-containing electrolytes. Nanoscale Adv 1: 33643371. 2019.

Churchill CD, Healey MA, Preto J, Tuszynski JA, Woodside MT: Probing the basis of α-synuclein aggregation by comparing simulations to single-molecule experiments. Biophys J 117: 11251135, 2019.

Klejborowska G, Moshari M, Maj E, Majcher U, Preto J, Wietrzyk J, Tuszynski JA, Huczyński A: Synthesis, antiproliferative activity and molecular docking studies of 4-chlorothiocolchicine analogues. Chem Biol Drug Des 95: 182-191, 2019.

Pagniez F, Lebouvier N, Na YM, Ourliac-Garnier I, Picot C, Le Borgne M, Le Pape P: Biological exploration of a novel 1,2,4-triazole-indole hybrid molecule as antifungal agent. J Enzyme Inhib Med Chem 35: 398403, 2020.

Haidar S, Marminon C, Aichele D, Nacereddine A, Zeinyeh W, Bouzina A, Berredjem M, Ettouati L, Bouaziz Z, Le Borgne M, Jose J: The discovery of naphtho[2,3-b]furane-4,9-dione as new backbone for the development of active CK2 inhibitors via a molecular modeling approach using indeno[1,2-b]indole entity. Molecules 25: E97, 2020.

Guillon J, Nim S, Moreau S, Ronga L, Savrimoutou S, Thivet E, Marchivie M, Di Pietro A, Prasad R, Le Borgne M: Synthesis of new piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of Candida albicans multidrug transporters by a Buchwald-Hartwig cross-coupling reaction. RSC Adv 10: 2915-2931, 2020.

 

Reviews

Raingeval C, Krimm I: NMR investigation of protein-ligand interactions for G-protein coupled receptors. Future Med Chem doi: 10.4155/fmc-2018-0312, 2019.

Issa S, Prandina A, Bedel N, Rongved P, Yous S, Le Borgne M, Bouaziz Z: Carbazole scaffolds in cancer therapy: a review from 2012-2018. J Enzyme Inhib Med Chem 34: 13211346, 2019.

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